1. Field of the Invention
This invention relates to silyl ether prodrugs containing at least one hydrophilic group on the silicon atom. The prodrugs hydrolyze at low pH, enabling release of the active drug in the gastric pH range. The invention further relates to a method of preparation of the silyl ether prodrugs, and to a method of treatment or prevention of gastric ulcers with a prodrug of misoprostol.
2. Related Background Art
It is known in the art that trialkylsilyl ether groups can be employed in pH-selective delivery systems for drug molecules. J. Chem. Soc. Perkin Trans., Vol. 10, p. 3043 (1992); J. Pharm. Sci., Vol. 77, p. 116 (1988); Int. J. Pharm., Vol. 28, p. 1 (1986); J. Pharm. Sci., Vol. 71, p. 1 (1982); Scientia Pharmaceutica, Vol. 43, p. 217 (1975); and JP 8,165,301. In these references, prodrugs containing trialkylsilyl ethers were formed from hydroxyl-containing drugs and found to undergo hydrolysis to release the drug only at low pH values. Such systems are of particular interest for selective delivery of drugs to the stomach, where pH values are typically in the range from 1 to 4. When any remaining prodrug passes into the intestine, where pH values are typically about 7, release of the drug ceases, thus avoiding the side effects usually associated with intestinal absorption.
Trialkylsilyl ethers formed at one or more of the hydroxyl groups of drugs in the prostaglandin series are also well known. In U.S. Pat. No. 3,965,143, a triethylsilyl ether is formed at position 16 of misoprostol, a prostaglandin drug. In U.S. Pat. Nos. 5,055,604 and 5,075,478, and in ES 545634, the 11-triethylsilyl ether of misoprostol is formed. U.S. Pat. No. 5,252,763 discloses a process for making a trialkylsilyl ether, in which the alkyl groups contain from 1 to 6 carbon atoms, at the 11 position of misoprostol. Finally, PCT Application No. WO 96/28419 discloses a trialkylsilyl ether at the 11 position, in which the alkyl groups contain from 1 to 8 carbon atoms. In all of the aforementioned references, the trialkylsilyl ethers are disclosed only as intermediates in the synthesis of prostaglandins. No suggestion is made that these compounds would be useful as delivery systems for prostaglandins, or that hydrophilic groups be substituted for the alkyl groups in the trialkylsilyl ether.
A polymeric delivery system in which a drug, such as a prostaglandin, is covalently bonded through a hydroxyl substituent, and is selectively released at a predetermined pH is described in PCT Application No. WO 92/01477; U.S. Pat. No. 5,474,767; and Journal of Medicinal Chemistry, Vol. 36, p. 3087 (1993). The pH-selective drug delivery systems described in these references comprise a drug covalently bonded to a linker by reaction with a silyl chloride functional group on the linker, thus forming an acid-sensitive silyl ether bond, and a polymer which is covalently bonded to the linker-drug combination. The polymer is crosslinked following bonding of the linker, or in some cases, prior to bonding of the linker. In an acidic environment, the silyl ether bonds hydrolyze, allowing the drug molecules to diffuse from the polymer matrix. However, unlike many prodrugs, the polymer-bound drug has no significant hydrophilic nature. No suggestion is made in these references to attach a hydrophilic group to the drug.